2. Academic Validation
  3. Spermine enhances antiviral and anticancer responses by stabilizing DNA binding with the DNA sensor cGAS

Spermine enhances antiviral and anticancer responses by stabilizing DNA binding with the DNA sensor cGAS

  • Immunity. 2023 Jan 26;S1074-7613(23)00011-0. doi: 10.1016/j.immuni.2023.01.001.
Lina Wang 1,  Siru Li 1,  Kai Wang 1,  Na Wang 1,  Qiaoling Liu 1,  Zhen Sun 1,  Li Wang 2,  Lulu Wang 3,  Quentin Liu 4,  Chengli Song 5,  Qingkai Yang 6
Affiliations

Affiliations

  • 1 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China.
  • 2 CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China.
  • 3 School of Life Science and Biotechnology, Dalian University of Technology, No. 2 Linggong Road, Dalian, Liaoning 116024, China.
  • 4 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
  • 5 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China. Electronic address: [email protected].
  • 6 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, Liaoning 116044, China. Electronic address: [email protected].
PMID: 36724787 DOI: 10.1016/j.immuni.2023.01.001
Abstract

Self-nonself discrimination is vital for the immune system to mount responses against pathogens while maintaining tolerance toward the host and innocuous commensals during homeostasis. Here, we investigated how indiscriminate DNA sensors, such as Cyclic GMP-AMP Synthase (cGAS), make this self-nonself distinction. Screening of a small-molecule library revealed that spermine, a well-known DNA condenser associated with viral DNA, markedly elevates cGAS activation. Mechanistically, spermine condenses DNA to enhance and stabilize cGAS-DNA binding, optimizing cGAS and downstream Antiviral signaling. Spermine promotes condensation of viral, but not host nucleosome, DNA. Deletion of viral DNA-associated spermine, by propagating virus in spermine-deficient cells, reduced cGAS activation. Spermine depletion subsequently attenuated cGAS-mediated Antiviral and Anticancer immunity. Collectively, our results reveal a pathogenic DNA-associated molecular pattern that facilitates nonself recognition, linking metabolism and pathogen recognition.

Keywords

DNA condensation; DNA sensing; cGAS; phase separation.

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